PROJECT SUMMARY/ABSTRACT Description. Our goal is to study the feasibility of a new nanotechnology to achieve more efficient and safer anti-viral drug delivery across the blood-brain barrier (BBB) for improved treatment of human immunodeficiency virus (HIV)-associated neurocognitive disorder (HAND). Despite the extensive use of antiretroviral (ARV) drugs, there remain over 35 million of people in the world living with HIV and more than half of the patients have neurological complications known as HAND caused by the persistence of HIV residing in the brain compartment. The current ARV therapy cannot significantly lower the prevalence of HAND partly contributed by the inefficiency of ARV compounds to cross the BBB to reach desirable brain drug levels. In this application, we will address this issue by exploring a novel yet simple and safe brain-targeting nanodelivery strategy. Docosahexaenoic acid (DHA) is an oil highly enriched in the brain and sufficient amount of it is naturally required for proper brain development and function. A recent study published in Nature indicates that Mfsd2a, a membrane transporter exclusively expressed in the endothelium of the BBB micro-vessels, is responsible for the import of DHA from the blood circulation into the brain. We propose that a lipid-based nanocarrier incorporating sufficient DHA, known as nanoARV, can enhance the delivery of ARV drugs across the BBB by exploiting this Mfsd2a pathway, thereby helping these drugs to achieve therapeutic levels in the brain compartment for effective HIV eradication. Driven by this hypothesis, we will aim to (1) develop DHA- based nanocarriers entrapping ARV drug with optimal physicochemical properties and stability, (2) evaluate the impact of DHA incorporation in nanocarrier for enhancement of ARV delivery across BBB cell model and verify the involvement of Mfsd2a in this process, and (3) study the feasibility to achieve favorable in vivo brain accumulation of ARV when delivered by a DHA-based nanocarrier. Successful completion of the proposed study will validate an easy-to-implement strategy for brain delivery of drugs, and help develop a medical device that is efficient enough to carry high concentrations of ARV across BBB for effective HAND treatment while remaining harmless enough even reaching a high brain level. Relevance to Public Health. In North America only, more than 1.1 million people are living with HIV and the majority of them are affected by HIV-associated neurocognitive disorder to different degree, and this causes substantial reduction of their life quality and also imposes a heavy burden on the public health system. The current drug therapy of HIV fails to significantly reduce the prevalence of this complication because of the inefficiency of anti-viral drugs to reach into the brain. This application aims at developing a novel strategy to allow efficient and safe access of anti-viral drugs into the brain compartment, so the HIV proliferating there can be effectively eradicated to achieve a potential cure of this highly prevalent and costly group of diseases.